This project will provide critical preclinical data for a novel therapeutic small molecule inhibitor of plasminogen activator inhibitor 1 (PAI-1) as a potential treatment for diffuse cutaneous systemic sclerosis with associated interstitial lung disease (dcSSc-ILD). SSc is a devastating disease of unknown etiology with no currently approved disease-modifying treatments; lung fibrosis (interstitial lung disease, ILD) is the leading cause of mortality in dcSSc. In this application we will assess the clinical utility of a highly innovative first in class therapeutic. PAI-1 is the physiologic inhibitor of tissue and urokinase plasminogen activator (tPA and uPA). In normal physiology PAI-1 regulates processes such as fibrinolysis and wound healing. However, elevated expression of PAI-1 is associated with fibrotic diseases of the lung, kidney, heart, and importantly for this application, with SSc. This association has led to the recognition that PAI-1 contributes directly to pathology, and that its inhibition may be an effective approach to treat fibrotic disease. MDI Therapeutics has identified a series of highly effective, orally active, small molecule inhibitors of PAI-1 with efficacy in multiple models of fibrotic disease, including pulmonary fibrosis and SSc. The studies described in this Phase 1 application will compare the two top candidate molecules in this series, MDI-2268 and MDI-2517, with the primary goal of selecting the clinical candidate molecule for the IND-enabling studies that will be performed in Phase 2 of this SBIR. There are two specific aims with clear milestones that will effectively assess the clinical utility of these highly innovative first in class therapeutics. These milestones include comparing the two clinical candidates for efficacy in a murine model of SSc relative to the current treatment options; direct comparison of their pharmacokinetics properties, and their safety in 7 day multi-dose toxicology studies. The successful completion of these milestones will significantly advance this program toward commercialization by identifying a single lead clinical candidate to be selected for API synthesis and for the IND-enabling toxicology studies planned in Phase 2 of this SBIR.